Studies have been conducted on the kynurenine (KYN) pathway to characterize the relative importance to brain quinolinic acid (QA) concentrations of the in vivo synthesis of precursors versus their transport into the brain from systemic sources. Labeled (deuterated) KYN was infused to steady state in both normal and LPS immune-activated gerbils, followed by mass spectrometric and HPLC determination of the absolute endogenous concentrations of KYN and QA, as well as their labeled-to-unlabelled ratios, in brain, serum, kidney, lung, and liver. These studies were conducted to ascertain whether systemically synthesized kynurenine might always be the ultimate determinant of QA concentrations in brain given its potentially rapid microvascular transport across the brain capillary endothelium. Data was analyzed by a physiologic pharmacokinetic model of kynurenine metabolism in the brain, linked to the rest of the body via the plasma compartment. Multicompartment modeling of the systemic portion of the model is required to establish a relation between the plasma concentration of the hydroxy-KYN + hydroxyanthranilic acid intermediates and plasma QA. 78%, 100%, and 5% of brain KYN in controls, i.p. LPS-treated animals, and i.s. LPS-treated animals, respectively, was found to originate from blood. Hence only in i.s. LPS-treated animals was KYN primarily produced by local in vivo synthesis. In the case of brain QA in control animals, 48%, 7%, 35%, and 10% of QA originated, respectively, from blood QA, blood OH-KYN, blood KYN, and local synthesis from tryptophan. Similar percentages were found for i.p. treated animals. For i.s. treated animals, most QA (95%) originated from local synthesis.